| Background |
The actin-binding protein girdin (CCDC88A, GIV) is a non-receptor guanine nucleotide exchange factor (GEF) and part of a scaffold that mediates key signaling pathways during cell migration. Girdin protein structure includes an amino-terminal Hook domain for microtubule interaction, a coiled-coil dimerization domain, a Gα binding domain, a PI(4)P-binding domain, and a carboxy-terminal receptor-binding domain within a GEF motif. Akt kinase phosphorylates girdin at Ser1416, which promotes PI(4)P binding, localization of girdin to the membrane leading edge, and regulation of actin organization and cell motility. After growth factor receptor activation, girdin binds both G-protein and receptor to form an activation complex at the receptor cytoplasmic tail. The activation complex enhances receptor autophosphorylation and promotes downstream signaling that results in actin organization and cell migration. An activated growth factor phosphorylates girdin at its carboxy-terminal Tyr1764 and Tyr1798 residues to form an SH2 docking site for PI3K binding. The girdin GEF motif interacts with Gα and leads to release of Gβγ, resulting in further PI3K activation and the completion of signal transduction from receptor to cytoskeleton. The cytoskeletal reorganization and cell migration properties of girdin are important in regulating several biological processes, including wound healing, angiogenesis, and cancer progression.
|